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 Table of Contents  
Year : 2017  |  Volume : 1  |  Issue : 4  |  Page : 221-227

Dysbiosis of gut microbiota contributes to chronic stress in endometriosis patients via activating inflammatory pathway

1 Department of Obstetrics and Gynecology, Shanghai Medical School, Fudan University, Shanghai 200032, China
2 Department of Obstetrics and Gynecology, Shanghai Medical School, Fudan University; Department of Integrated Traditional Chinese and Western Medicine, Obstetrics and Gynecology Hospital, Fudan University; Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Shanghai 200011, China

Date of Submission27-Oct-2017
Date of Web Publication7-Feb-2018

Correspondence Address:
Yu Kang
Department of Obstetrics and Gynecology, Shanghai Medical School, Fudan University, No. 419 Fangxie Road, Shanghai 200011
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/2096-2924.224916

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Background: Gut microbiota can interact with the central nervous system through the gut–brain axis, thus affecting the host's chronic stress level, such as anxiety and depression. Current researches show that patients with endometriosis often have a high level of chronic stress, which will in turn aggravate endometriosis by activating the β-adrenergic signaling pathway. Therefore, we wondered whether the gut microbiota associates with the chronic stress level in endometriosis patients, which may provide new insights on how to improve treatment.
Methods: We grouped the endometriosis patients into the chronic stress group and the control group with questionnaires such as generalized anxiety disorder-7 and patient health questionnaire-9 and collected patients' fecal specimens and tissue specimens. Gut microbiota compositions were analyzed by the 16SrRNA gene sequencing-based method, and immunohistochemistry was performed to detect the activation of inflammatory pathways in endometriosis tissues.
Results: We found that in patients with endometriosis, the dysbiosis of gut microbiota was associated with their stress levels. Furthermore, the levels of Paraprevotella, Odoribacter, Veillonella, and Ruminococcus were significantly reduced in chronic stressed endometriosis patients, suggestive of a disease-specific change of gut microbiota at the genus level. Compared to the healthy women, the expression levels of inflammatory cytokines, nuclear factor-κB p65, and cyclooxygenase-2 increased in the chronic stressed endometriosis patients, indicating that the dysbiosis of gut microbiota may activate the inflammatory pathway of gut–brain axis.
Conclusions: We hypothesized that these new disease-specific changes of gut microbiota in chronic stressed patients with endometriosis may be a new examination target of chronic stress level. These changes may also provide new insights for psychological intervention, thus reducing the stress level and improving the prognosis of endometriosis patients.

Keywords: Chronic Stress; Endometriosis; Gut Microbiota; Gut-brain Axis

How to cite this article:
Xu J, Li K, Zhang L, Liu QY, Huang YK, Kang Y, Xu CJ. Dysbiosis of gut microbiota contributes to chronic stress in endometriosis patients via activating inflammatory pathway. Reprod Dev Med 2017;1:221-7

How to cite this URL:
Xu J, Li K, Zhang L, Liu QY, Huang YK, Kang Y, Xu CJ. Dysbiosis of gut microbiota contributes to chronic stress in endometriosis patients via activating inflammatory pathway. Reprod Dev Med [serial online] 2017 [cited 2022 Jan 18];1:221-7. Available from: https://www.repdevmed.org/text.asp?2017/1/4/221/224916

Jing Xu and Ke Li contributed equally to this work.

  Introduction Top

Gut microbiota is considered to be the “hidden organ” and the “second genome”.[1] Dysbiosis of gut microbiota can cause a series of diseases and may trigger endometriosis.[2] Although there are some differences in the composition of the gut microbiota in rhesus monkeys with endometriosis compared with the healthy monkeys, the specific mechanism is not clear.[3]

Gut microbiota not only has a local role in the intestinal tract but also a systemic role by penetrating through the intestinal mucosa.[4],[5] The gut–brain axis is one of the major pathways eliciting systemic effects.[5],[6],[7],[8] It mediates a bidirectional signal pathway [9] between the intestinal and the central nervous systems and mainly involves the immune,[10],[11] metabolic,[6],[12] neuroendocrine,[13],[14] and vagal neural pathways.[15],[16] Gut microbiota interacts with the central nervous system through the gut–brain axis, thus affecting the host's emotions and behaviors, such as anxiety and depression.[17],[18] The microbial community in major depressive disorder (MDD) patients could be changed and the proportion of probiotics decreased.[19],[20],[21] Animal model researches also support this theory.[22] Compared to healthy mice, there are significant differences in the gut microbiota of the mice with depression, which can be reduced by supplementing these mice with bifidobacteria.[22],[23]

Chronic stress, such as anxiety and depression, is related to the occurrence and development of endometriosis.[24] Clinical studies have found that patients with endometriosis often show a higher level of anxiety and depression,[25] De Graaff et al. reported that the incidence of anxiety and depression in patients with endometriosis was 44.6% and 18.1%, respectively, and that their levels were significantly higher than those in healthy controls.[26] Long et al. confirmed in experimental animals that psychological stress can promote endometriosis lesions by activating the β-adrenergic signaling pathway, which demonstrates the important role of chronic stress in the development of endometriosis.[27]

Therefore, we wonder whether the gut microbiota can affect endometriosis lesions by changing the host's chronic stress level through the gut–brain axis. Our experimental results showed that in patients with endometriosis, there was a link between the dysbiosis of gut microbiota and chronic stress. There was also a genus-specific difference in the gut microbiota of the chronic stressed patients with endometriosis. An inflammatory pathway within the gut–brain axis may be responsible for the association between the gut microbiota and chronic stress.

  Methods Top

Recruitment of patients

Patients with endometriosis were recruited from the Fudan University Affiliated Obstetrics and Gynecology Hospital. Psychological assessment scale waslisted as follows for the generalized anxiety disorder-7 (GAD-7) Scale: 0–4 as no anxiety, 5–9 as mild anxiety, 10–13 as moderate anxiety, 14–18 as moderate-to-severe anxiety, and 19–21 as severe anxiety; and for the patient health questionnaire-9 (PHQ-9) scale: 0–4 as anxiety/depression, 5–9 as mild depression, 10–14 as moderate depression, 15–19 as moderate-to-severe depression, and 20–27 as severe depression. Our assessment of the mental state of each patient was completed before the surgery, and each patient was informed of its purpose. The patients completed questionnaires with the help of researchers. We categorized patients with mild or higher levels of depression/anxiety as the chronic stress group and those without anxiety/depression or those with mild anxiety/depression as the control group.

Fecal specimens were collected before the surgery, placed in sterile tubes, and immediately frozen at −80°C for further microbial community analysis. Blood specimens were also collected before the surgery. They were centrifuged at 1,000 g for 10 min, and the serum was stored at −80°C. The norepinephrine concentration was measured by high-performance liquid chromatography.

16SrRNA analysis

Specimens were stored at −80°C before DNA extraction. DNA was isolated using the Soil DNA Kit (Omega, D5625-01). Its concentration was measured by an ultraviolet spectrophotometer (Eppendorf, Bio Photometer), and its molecular size was estimated by 0.8% agarose gel. To analyze the taxonomic composition of the gut microbiota community, the V3–V4 region of the 16SrRNA gene was chosen for subsequent pyrosequencing. Polymerase chain reaction (PCR) amplification was performed with the specific primers 520F (5'-GCACCTAAYTGGGYDTAAAGNG-3') with a unique barcode sequence and 802R (5'-TACNVGGGTATCTAATCC-3') using the following conditions: 98°C for 5 min (initial denaturation); 98°C for 10 s; 50°C for 30 s; 72°C for 30 s (25–27 cycles); and 72°C for 5 min (final extension). The purified amplicons were quantified on Microplate reader (BioTek, FLx800) with Quant-iT PicoGreen dsDNA Assay Kit (Invitrogen, P7589) and then pooled together. Samples were normalized in equimolar amounts in the final mixture. The DNA library preparation followed the manufacturer's instructions (Illumina). End-repaired process adds 5'-phosphate groups needed for downstream ligation using an End Repair Mix (Illumina). DNA fragments that have adapter molecules on both sides were enriched by PCR amplification. We performed mate-pair sequencing on 2 × 300 base pairs (bp) with MiSeq Reagent Kit v3 (600-cycles-PE) (Illumina, MS-102-3003) for the libraries on Miseq. Taxonomic identifications were assigned using BLAST searches against the Greengenes bacterial 16S rRNA database (UNITE fungal database and SILVA database) at a minimum e-value threshold of 0.001.


Tissue samples were fixed in 10% formalin (w/v) and paraffin-embedded. Serial sections with a thickness of 4 μm were obtained from each block, and the first slide was stained with hematoxylin and eosin to confirm the histologic diagnosis. The subsequent slides were used for the staining of nuclear factor-κB (NF-κB) p65 and cyclooxygenase-2 (COX-2).

Routine deparaffinization and rehydration procedures were performed. For antigen retrieval, slides were heated at 98°C in citrate buffer (G1202, Servicebio, Wuhan, China, pH 6.0) for 25–30 min, and then cooled gradually to room temperature. The NF-κB p65 and COX-2 antibodies were purchased from Cell Signaling Technology (Cat. 8242T, 12282T, respectively). The diluted concentrations were 1:400 for the NF-κB p65 antibody and 1∶350 for the COX-2 antibody. The sections were incubated with primary antibody overnight at 4°C. After the slides were rinsed, the HRP-labeled Secondary Antibody Detection Reagent (Sunpoly-HII, BioSun Technology Co., Ltd., Shanghai, China) was incubated at room temperature for 30–45 min. The bound antibody complexes were stained with diaminobenzidine (Cell Signaling Technology, Cat. 8059) for 3 min or until a signal was visible, counterstained with hematoxylin (G1004, Servicebio, Wuhan, China) for 30–45 s, and then mounted.

  Results Top

The serum norepinephrine level in chronic stress and control groups

We grouped the endometriosis patients [Table 1] into chronic stress and control groups using GAD-7 and PHQ-9 questionnaires. Our results showed that there was no significant difference in the serum norepinephrine level in the patients of chronic stress group compared with those of the control group [Supplementary Figure S1].
Table 1: Characteristics of endometriosis patients with chronic stress and without chronic stress*

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Correlation of chronic stress and dysbiosis of gut microbiota

The composition of the gut microbiota was analyzed by the 16SrRNA gene sequencing-based method. To compare microorganism community patterns in patients of both groups, principal coordinates analysis (PCoA) was performed. The PCoA score plot from sequences at the operation taxonomy units level with >97% similarity showed that the community composition of the chronic stress group was away from that of the control group [Figure 1]a. Moreover, at the genus level, there were significant differences in Paraprevotella, Odoribacter, Veillonella, and Ruminococcus with reduced levels in chronic stressed endometriosis patients [Figure 1]b. The previous research has shown the prevalence of Prevotella increased in MDDs patients,[28] which is in agreement with our results [Figure 1]c. The prevalence of Prevotella is higher in the chronic stressed patients than in the healthy controls. Data on the species abundance at different taxonomic levels are shown in [Supplementary Figure S2] and [Supplementary Figure S3
Figure 1: (a) Principal coordinates analysis score plots of operation taxonomy units between the chronic stress and control groups. (b) Difference of abundance at the genus level in the chronic stress and control group. (c) Difference in proportion of Prevotella.

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Inflammatory pathway of the gut–brain axis is activated in patients with dysbiosis of gut microbiota

The gut–brain axis consists of hypothalamic–pituitary–adrenal (HPA)[13],[14] axis, vagus nerve,[15],[16] inflammatory cytokines,[10],[11] and metabolic molecules [6],[12] such as short-chain fatty acids. We detected the inflammatory cytokines, NF-κB p65, and COX-2. The dysbiosis of gut microbiota can trigger inflammatory bowel diseases by activating the NF-κB pathway.[29],[30] In addition, lipoteichoic acid can affect the microenvironment of tumors by increasing the level of prostaglandin E2 through COX-2 pathway and then promoting the development of hepatocellular carcinoma.[31] Compared to the control group, the expression levels of NF-κB p65 [Figure 2]a and [Figure 2]b and COX-2 [Figure 2]c and [Figure 2]d increased in the chronic stressed patients. Therefore, we concluded that the dysbiosis of gut microbiota activates an inflammatory pathway of the gut–brain axis. NF-κB has been shown to be constitutively activated in endometriosis and growing evidence has shown that NF-κB is involved in many aspects of the development of endometriosis, including inflammation, proliferation, angiogenesis, oxidative stress, and invasion,[32],[33],[34] while COX-2 is also reportedly involved in endometriosis.[35] Therefore, we raised a hypothesis that dysbiosis of gut microbiota may affect the endometriosis through inflammatory pathway of gut–brain axis, which needs more evidence.
Figure 2: (a) Scatter plot of immunostaining levels of nuclear factor-?B. (b) Immunohistochemical staining of nuclear factor-?B in ectopic lesions in different groups. (c) Scatter plot of immunostaining levels of cyclooxygenase-2. (d) Immunohistochemical staining of cyclooxygenase-2 in ectopic lesions in different groups.

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  Discussion Top

The gut microbiota affects the host's mood and behavior through the gut–brain axis,[9],[22],[36] thus increasing the chronic stress level which is a key influencing factor of endometriosis.[24],[27],[37] Therefore, we wanted to explore whether the gut microbiota can change the stress level of endometriosis patients through the gut–brain axis and whether these changes can induce endometriosis lesions. Our results demonstrate that there is a correlation between the gut microbiota and chronic stress in endometriosis patients and that the dysbiosis of gut microbiota may act on the host's mood and behavior through the inflammatory cytokines pathway of gut–brain axis.

The most classic mechanism of chronic stress is HPA axis and sympathetic nervous systems pathway by releasing catecholamines and cortisol.[38],[39],[40] We used GAD-7 and PHQ-9 questionnaires to measure the stress status of each patient. Patients were divided into stress group and control group according to questionnaire scores, and the serum norepinephrine level was measured. We found that there was no statistically significant difference in its level between groups. The accuracy of our grouping methods might have been affected at a certain extent because the method that we used to group the patients was based on questionnaires, which are susceptible to subjective factors. However, the use of questionnaires to assess whether patients have chronic stress or not is the most widely used clinical method. Therefore, this method is still reliable. Alternatively, the number of patients might have contributed to the lack of differences between groups.

The composition of the fecal microbiota was analyzed by 16SrRNA gene sequencing-based method. PCoA analysis showed that there were some differences in the colony structure between the chronic stress group and the control group. Although there were also differences between individuals of the chronic stress group, this group was away from the control group, indicating that there are actually some differences in community structure. As the living environment, diet, etc., are likely to affect the host's gut microbiota,[41],[42] differences in groups are inevitable, especially when the sample size is not large enough. Furthermore, clustering analysis at genus level showed the proportion of Prevotella was significantly increased in chronic stressed patients, which was also reported previously in MDD patients.[28] In addition, we also found more significant differences in the proportions of Paraprevotella, Odoribacter, Veillonella, and Ruminococcus compared to Prevotella. Changes in the gut microbiota are different in different diseases. Thus, changes in MDD patients are expected to be different from chronic stressed patients with endometriosis. As a result, we conclude that these four species may be specific to the stress state in endometriosis patients.

The association between the dysbiosis of gut microbiota and the host's stress status is mainly through the gut–brain axis, and this axis mainly includes HPA axis, vagus nerve, inflammatory cytokines, and metabolic pathways. Therefore, we detected the inflammatory cytokines NF-κB p65 and COX2. We found the expression of the inflammatory cytokines was significantly higher in chronic stressed group than in the control group, indicating that the immune pathway of gut–brain axis was activated in stressed patients. We also found that the imbalance of Paraprevotella, Odoribacter, Veillonella, and Ruminococcus is associated with the stress state of the host through the inflammatory pathway of gut–brain axis.

In this study, we first explored the association between the gut microbiota and the stress status in endometriosis patients, and looked for specific changes of the gut microbiota associated with chronic stress, the adverse factor of endometriosis, hoping that we can provide an auxiliary method for the clinical improvement of the prognosis of patients with endometriosis. A published study has shown that the proportion of Prevotella is significantly higher,[28] and our data confirmed this result. In addition, we also found four additional species whose changes were more distinct than Prevotella in stressed endometriosis patients. This conclusion suggests that chronic stress such as anxiety and depression can lead to similar changes in the gut microbiota, expect that in different diseases, there may be specific changes of the gut microbiota that is associated with the disease. Thus, finding different disease-specific changes in the gut microbiota may provide new insights on clinical intervention. Endometriosis patients often show a higher level of anxiety and depression because of abdominal pain and infertility.[43] Anxiety, depression, and other psychological stress can also activate the β-adrenergic signaling pathway, thus leading to endometriosis lesion growth.[24],[27] Therefore, if we can identify the specific changes of the gut microbiota associating with chronic stress in endometriosis patients, we can produce from the results an adjuvant therapy method for psychological intervention, thus reducing the stress level and improving the prognosis.

There are also studies about specific changes of the gut microbiota in different diseases, such as cirrhosis,[44],[45] colon cancer,[46],[47],[48] and breast cancer.[49],[50] For example, there is a research studying the association of changes of the gut microbiota with anxiety and depression in breast cancer patients,[51] but no one has studied the specific changes of the gut microbiota and chronic stress in patients with endometriosis. This is the first study ever to address the relationship between specific gut microbiota changes and the chronic stress status in endometriosis patients. Endometriosis is closely related to chronic stress,[24],[25],[26] and a study of how the stress level can be reduced in patients with endometriosis has important clinical significance. The method used to assess the level of chronic stress in patients is mainly based on questionnaires, which is a subjective method. To improve the objectivity of the assessment method, the level of major chronic stress-related factors such as norepinephrine, cortisol was assessed by blood tests. However, blood test is an invasive examination, so the examination of fecal samples measures can replace the blood test and be used to assess the stress level in patients, that is, if we find chronic stress-specific gut microbiota changes. Although specific oral probiotics may remodel the gut microbiota, patients may be benefit from assisted clinical psychological intervention. Together, they may reduce the level of stress and improve the prognosis of patients.

The main drawback of this study was that the number of samples collected was not enough, inducing the individual diversification within the same group. Nevertheless, further studies are needed to address the roles of the four pathways of the brain-gut axis.

Supplementary information is linked to the online version of the paper on the Reproductive and Developmental Medicine website.

Financial support and sponsorship

This work was supported by the National Key R&D Program of China (2016YFC1303100); the National Natural Science Foundation of China (81472423); Shanghai Medical Center of Key Programs for Female Reproductive Diseases (2017ZZ01016); Shanghai Municipal Health and Family Planning Commission (ZYKC201701020).

Conflicts of interest

There are no conflicts of interest.

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